Intravaginal drug delivery device

ABSTRACT

An intravaginal drug delivery device comprising at least one active agent dispersed in a polymer matrix, wherein the concentration of active agent at the outer surface of the device at the time of use is not substantially higher than the concentration of the active agent in the remainder of the device, a method of treatment therewith and a process for its preparation.

PRIOR APPLICATION

This application is a division of U.S. patent application Ser. No.09/102,302 filed Jun. 22, 1998, now U.S. Pat. No. 6,039,968.

STATE OF THE ART

The present invention relates to intravaginal drug delivery devices. Inparticular, it relates to such devices suitable for the administrationof a therapeutic agent, such as an oestrogen and/or a progestogen, at asubstantially constant rate over a prolonged period of time, for examplein the treatment of oestrogen deficiency or in a method ofcontraception.

17β-oestradiol (E₂) is the principal oestrogen produced by thefunctioning pre-menopausal ovary during each menstrual cycle. With theageing process, ovulation becomes less frequent, resulting in diminishedproduction of E₂. At the menopause, E₂ production decreases dramaticallyto less than 20 μg per day. Oestrogen deficiency can also occur in thepre-menopausal female as a result of disease, traumatic injury oroophorectomy.

Oestrogens, in particular 17β-oestradiol, are widely used for treatingoestrogen deficiency, the aim being to replace endogenous oestrogenslost due to ovarian failure. Of the naturally occurring oestrogens,17β-oestradiol (E₂) has the best therapeutic profile for OestrogenReplacement Therapy (ERT) and Hormone Replacement Therapy (HRT) and hasbeen found to have an especially low incidence of side effects. Inparticular, 17β-oestradiol does not stimulate clotting factor synthesisand is not associated with an increased risk of venous thrombosis.17β-oestradiol and its semi-synthetic esters are therefore widely usedin the treatment of disorders associated with oestrogen deficiency, inparticular menopausal and post-menopausal symptoms.

Oestrogens and progestogens are also widely used in methods ofcontraception.

When taken orally, steroids in general are not particularly wellabsorbed, although after micronisation reasonable systemic levels can beachieved. Oral administration is followed primarily by absorptionthrough the gastrointestinal tract from where the blood flow is to theliver. In general, oestrogens and progestogens have a high first passand about 50 to 70% is metabolised during the first pass through theliver. As a result, oral therapy results in low bioavailability.Moreover, oral oestrogen therapy results in the formation of oestrone, aless potent oestrogen, which influences the blood lipid profile. Thisalso means that there is about a 30% reduction in availability ofoestrogen due to the first pass effect.

A further disadvantage associated with the oral administration ofsteroids is that it involves bolus doses resulting in undesirably highplasma levels after each dose and the need for frequent dosing.

An alternative to oral administration is subcutaneous implantation ofoestrogen or progestogen-containing pellets, rods or oils. However, thisrequires medical supervision. For the delivery of oestrogen, transdermaldrug delivery systems have also been proposed. However, these are notcapable of producing the levels of oestrogen required for long termtherapy and must be replaced every few days. Subcutaneous implantsrequire surgical insertion and removal and are difficult to remove ifdangerous side effects develop. Moreover, neither of these methods iscapable of producing the constant levels of oestrogen or progestogennecessary for the treatment of oestrogen deficiency or for contraceptiveuse over a long period of time.

Vaginal administration of steroids overcomes a number of the problemsassociated with oral delivery. It is well known that steroids ingeneral, including oestrogens and progestogens, are efficiently andrapidly absorbed through the vaginal mucosa. Moreover, delivery ofoestrogen into the vagina is analogous to the secretion of oestrogeninto the blood stream by the ovary and avoids undesirable first passmetabolism by the liver.

Oestrogen may be administered intravaginally using creams, solutions ortablets. However, as with oral administration, these result in bolusdelivery rather than sustained levels of oestrogen and require repeatedapplication. In order to achieve controlled, sustained release ofoestrogen over a period of months, an intravaginal device, convenientlyin the shape of a ring, has proved to be most effective. A particularadvantage associated with the use of vaginal rings is that these can beself-inserted into and removed from the vagina.

There are three main types of ring design. The first is the matrix ringin which the active ingredient is distributed throughout a hydrophobicelastomeric system. The rate of release of active from a ring of thisparticular design is expressed by the equation given below (Chien 1985):##EQU1## where: Q=amount of active released per unit area

A=concentration of the active in the matrix

Cp=solubility of active in the matrix

Dp=diffusion coefficient of the active in the matrix

t=time

The second type of ring design is the core design in which the activeingredient is dispersed in a polymer matrix core surrounded by arate-controlling sheath. The rate of drug release from a ring of thistype can be expressed by the following equation (Crank 1967): ##EQU2##where: R=release rate

Cs=saturation solubility of active in the polymer matrix

D=diffusion coefficient of active in the polymer matrix

b=diameter of the sheath

a=diameter of the core

L=length of the core

The third type of ring is the shell design in which the drug iscontained in a narrow band between a non-medicated central hydrophobicelastomeric core and an outer sheath. The outer sheath acts as arate-controlling membrane.

When using intravaginal devices for the delivery of therapeutic agents,it is desirable that the agent is released at a substantially constantrate over a prolonged period of time, preferably in the absence of highlevels of release of the agent, particularly preferably in the absenceof any initial high burst of agent during the first 24 hours followingvaginal administration. This is particularly so when using such a devicefor the treatment of oestrogen deficiency or in a method ofcontraception.

In the case of rings of the matrix design, high initial loading with anactive agent is possible, resulting in an initial high dose of activefollowed by a gradual decrease in the release rate. The rate of releaseof active agent over the first 2 or 3 weeks is also unacceptably high.Whilst intravaginal rings having a core or shell design are capable of anear zero order release of active, these too are characterised by anunacceptably high initial burst of active during the first 24 hoursand/or over the first 15 or 21 days followed by a gradual decline to thedesired release level. This high level of release of active in the first24 hours and thereafter during the first 15 to 21 days can be associatedwith side effects which, depending on the nature of the active, may beserious. Thus, for example in the case of administration of17β-oestradiol, an initial dose in excess of 700 μg over a period of 24hours can cause increased risk of venous thrombosis.

OBJECTS OF THE INVENTION

There thus exists a need for intravaginal drug delivery devices capableof releasing an active or actives, such as oestrogen, in a substantiallyzero order pattern on a daily basis over a period of several months inthe absence of any initial high rate of release of active.

BRIEF SUMMARY OF THE INVENTION

It has now surprisingly been found that wrapping an intravaginal drugdelivery device with a removable polymer membrane is able tosubstantially reduce not only the initial high burst of active from thedevice following administration, e.g. during the first 24 hours of use,but also the levels of release of active during the first 3 weeks ofuse.

Thus, viewed from one aspect the invention provides an intravaginal drugdelivery system having a first part intended for intravaginaladministration ("an intravaginal part") comprising at least one activeagent, such as an oestrogen and/or a progestogen, in a polymer matrix,said first part being provided in association with a second partcomprising a removable polymer membrane arranged to absorb excess activeagent.

By "removable" it is intended that the polymer membrane is arranged suchthat this can readily be removed from the intravaginal part by thepatient or the physician prior to use or, alternatively, as anintermediate step during the manufacturing process. Conveniently,removal of the membrane may be achieved by simply tearing away thepolymer membrane, for example along pre-formed tear lines orperforations provided in the membrane.

The polymer membrane may surround the intravaginal part either wholly orsubstantially. Preferably, the membrane wholly surrounds theintravaginal part.

Whilst not wishing to be bound by theoretical considerations it isbelieved that the initial high level of active released from vaginalrings of the core or shell design is a result of diffusion of the activefrom the surface of the core into the surrounding sheath during storage.This in turn results in an artificially high concentration gradient ofactive across the sheath and very close to the outer surface of thering. Such an accumulation of active close to the surface of the ring isin excess of that which can be modelled using a matrix typedistribution.

Similarly, it is believed that the high initial burst of active fromrings of the matrix design is a result of a high level of active presenton the surface of the ring. In these rings, the active is thus alsobelieved to be present in much greater amounts at the outer surface ofthe ring.

Again not wishing to be bound by theory, it is believed that the polymermembrane serves to remove excess quantities of active from the surfaceof the intravaginal part of the system. This enables delivery ofsustained, therapeutic quantities of active agent over extended periodsof time, such as required in the delivery of oestrogen in EstrogenReplacement Therapy (ERT) and Hormone Replacement Therapy (HRT) or inthe delivery of estrogens and progestogens in contraception, without anyinitial high burst of active.

In serving to effectively remove the high concentration of active at theouter surface of the intravaginal part of the system, the invention iscapable of providing an intravaginal delivery device in which the activeor actives are more homogeneously dispersed therein. Preferably, theactive agent is substantially homogeneously dispersed throughout thepolymer matrix.

Thus, viewed from another aspect the invention provides an intravaginaldrug delivery device comprising at least one active agent, such as anoestrogen and/or a progestogen, dispersed in a polymer matrix, whereinthe concentration of active agent at the outer surface of the device atthe time of use is not substantially higher than the concentration ofthe active agent in the remainder of the device. Preferably, the activeis substantially homogeneously dispersed throughout the device.

Yet more preferably, the concentration of active agent at the outersurface of the device is substantially lower than the concentration ofthe active agent in the remainder of the device. Thus, preferably theactive is substantially homogeneously dispersed throughout the device,other than in close proximity to the surface.

Whilst it will be appreciated that the precise shape and dimensions ofthe polymer membrane will depend on the geometry of the device, themembrane should preferably be arranged such that this forms a relativelytight fit with the intravaginal part of the system. Thus, the polymermembrane should generally correspond to the shape of the intravaginalpart. For example, in the case of a ring-shaped device the membrane willconveniently be toroidal in shape and its dimensions will be such thatthis lies in close contact with the outer surface of the intravaginalpart.

The polymer membrane may be in direct contact with the intravaginalpart. However, contact between the polymer membrane and the intravaginalpart may be improved by smearing or coating the intravaginal part,either wholly or substantially, with an inert lubricant, e.g. alubricating oil such as silicone, prior to wrapping with the polymermembrane. Examples of lubricants other than silicone which may be usedto coat the intravaginal part prior to wrapping include othernon-oxidising oils known to those skilled in the art. The use of alubricant to coat the intravaginal part prior to wrapping also serves toaid ready removal of the polymer membrane by the patient or physicianprior to use. Conveniently, any lubricant is removed from theintravaginal part, e.g. by washing, before use.

The polymer membrane may comprise any polymer material capable ofabsorbing an active from the intravaginal part and those skilled in theart will be aware of particular polymer materials suitable for thispurpose. Whilst the particular choice of polymer for use as a membranematerial will clearly depend on the active or actives to be delivered,polymers particularly suitable for use as a membrane material are thosehaving a water vapour transmission (measured at a temperature of 20° C.,a relative humidity of 85% and a film thickness of 50 μm) in the rangeof from 1 to 10,000 g/m².d, more preferably from 1 to 300 g/m².d, e.g.from 1 to 100 g/m².d (wherein d=24 hours).

In general, any biocompatible polymer or mixture of such polymers may beused as the membrane material. Particularly suitable polymer materialsinclude polyolefins such as polyethylene, polypropylene andpolymethylpentene. Other polymers which may be used as the membranematerial include polyvinylchloride, polyurethanes, polyamides andsilicone elastomers such as organopolysiloxanes. Particularly preferredpolymers are organopolysiloxanes, such as polydimethylsiloxanes andpolyvinylmethylsiloxanes or mixtures thereof, optionally containing oneor more fatty acid esters.

The thickness of the polymer membrane for use in accordance with theinvention is dependent upon a number of factors, including the size,shape and specific design of the device, the amount and type of drugpresent in the device, and the period over which the device is intendedto be stored in the membrane prior to use. Whilst those skilled in theart can readily determine the desired thickness for the polymer membranefor any given device, this will conveniently lie in the range of from 10to 3000 μm, preferably from 10 to 2000 μm, more preferably from 30 to1000 μm, e.g. from 30 to 100 μm.

As mentioned above, the thickness of the polymer membrane will bedetermined by the design of the ring, i.e. whether this is of thematrix, core or shell design. The membrane will be thickest for use witha matrix-type ring where a thickness of from 10 to 3000 μm is preferred.In the case of the core and shell designs, the use of a much thinnermembrane is possible, e.g. one having a thickness of from 10 to 2000 μm.

The polymer matrix and polymer membrane may comprise one or morebiocompatible polymers, for example elastomers such asorganopolysiloxanes. Preferred elastomers include hydroxyl-terminatedorganopolysiloxanes of the RTV (room temperature vulcanizing) type whichharden to elastomers at room temperature following the addition ofcross-linking agents in the presence of curing catalysts. Suitablecross-linking agents and curing catalysts are known in the art. Atypical curing catalyst is stannous octoate. Curing temperature andcuring times can vary within broad ranges and depend on the particularelastomer used. The curing temperature may vary between room temperatureand 150° C., but is preferably within the range of from 60 to 90° C. Thecuring time may vary between a few seconds to several hours.

Other suitable elastomers include two-component dimethylpolysiloxanecompositions which are platinum catalysed at room temperature or underelevated temperatures and capable of addition cross-linking.

Preferred hydrophobic elastomers for use either as the polymer matrix orthe polymer membrane material in the device according to the inventioninclude Silastic 382® and Silastic 4210®, both commercially availablefrom Dow Corning.

In a preferred embodiment of the invention, the intravaginal part of thedevice comprises a polymer matrix surrounded by a rate-controllingsheath through which the active can diffuse and which controls the rateof diffusion of active from the device into the vagina.

In a further embodiment of the invention, the intravaginal partcomprises a core of inert elastomer, an active-containing polymer matrixencircling the core and an outer rate-controlling sheath through whichthe active can diffuse.

The sheath may comprise any bio-compatible polymer. Conveniently thiswill comprise the same polymer as the polymer matrix.

The polymer matrix and/or the rate-controlling sheath may furthercomprise one or more filler materials, such as diatomaceous earth orsilica. In addition, the polymer matrix may comprise an X-ray contrastmedium, such as barium sulphate, which can be used for identificationpurposes.

The polymer matrix, polymer membrane and/or the rate-controlling sheathmay further comprise one or more rate modifying agents, such as a fattyacid ester, preferably one containing from 2 to 20 carbon atoms.

Preferred fatty acid esters for use in the device according to theinvention include those formed from acids containing from 2 to 20 carbonatoms, especially long chain fatty acids, e.g. caproic, lauric,myristic, oleic, linoleic, adipic and lanolic acids. Particularlypreferred are those esters formed from myristic acid. Alcohols which maybe used in the formation of the esters include those containing from 2to 20 carbon atoms, particularly those containing from 2 to 4 carbonatoms, e.g. propanol, in particular, isopropanol. A particularlypreferred fatty acid ester is isopropyl myristate.

The amount of fatty acid ester present in the device will clearly dependupon the particular active to be delivered as well as the condition tobe treated. Conveniently, the amount of fatty acid ester present in thedevice is from 1 to 50% by weight, preferably from 5 to 20% by weight.By suitable adjustment of the level of fatty acid ester present in thepolymer matrix, a range of doses of active from rings of similargeometry can be achieved.

Whilst it should be apparent that the intravaginal device in accordancewith the invention may have any shape and dimensions compatible withintravaginal administration, a preferred device according to theinvention is in the form of a ring. This conveniently comprises acentral annular polymer matrix core surrounded by an annularrate-controlling sheath.

Conveniently, the overall diameter of the ring is in the range of from52 to 62 mm, with a sheath diameter (cross-sectional diameter of thering) in the range of from 4 to 10 mm and a core diameter in the rangeof from 1 to 9 mm. The thickness of the rate-controlling sheath is suchthat it can be manufactured within acceptable tolerances by methodsknown in the art and conveniently lies within the range of from 1 to 4mm, particularly from 1 to 3 mm. The geometry of the ring may beselected depending on the required daily dose of active and the durationof the course of treatment.

The intravaginal drug delivery device in accordance with the inventionis considered to have utility in connection with the delivery of a widerange of therapeutic agents. As used herein, the terms "active" and"active agent" are used interchangeably and are intended to define anysubstance which in vivo is capable of producing a desired, usuallybeneficial, effect and may be an agent having either a therapeutic or aprophylactic effect.

Examples of active agents suitable for use in the device of theinvention include agents in all of the major therapeutic areasincluding, but not limited to, anti-infectives such as antibiotics,antiviral and antifungal agents, analgesics, antidepressants, hormonesand vitamins.

It will be appreciated that the desired amount of active agent presentin the device will depend on the particular active being administered aswell as the condition being treated. Convenient amounts of active, suchas oestrogen, present in the device are from 1 to 50% by weight,preferably up to 15% by weight, more preferably from 5 to 15% by weight.

Conveniently, the device according to the invention can be used toeffectively treat a number of conditions resulting from oestrogendeficiency, e.g. vasomotor symptoms associated with oestrogendeficiency, atrophic vaginitis, atrophic urethritis and osteoporosisassociated with oestrogen deficiency. The device is particularlyeffective in hormone and oestrogen replacement therapies. Sincefertility control involves the administration of sufficient oestrogen orprogestogen to prevent ovulation, it will be appreciated that thedelivery device-of the invention may also be used to prevent ovulationand thus act as an effective contraceptive. In this regard, the activemay comprise one or more contraceptive steroids selected from ethinylestradiol, levonorgestrel, d,l-norgestrel and norethindrone.

Oestrogens which can be delivered vaginally using the device accordingto the invention include oestrone and oestriol, in particular17β-oestradiol which is widely used in hormone replacement therapy(HRT). Constant, daily release rates up to 500 μg per day for a periodof up to 12 months can be achieved using a device in accordance with theinvention. The desired rate of release of oestrogen depends on thecondition to be treated but can be varied over a range of from 10 to 200μg per day. A physiologically effective dose of 17β-oestradiolsufficient to treat postmenopausal symptoms is considered to be of theorder of at least 50 μg per day. For use as a contraceptive device, 20μg per day of levonorgestrel may be delivered.

Women who have undergone a hysterectomy with or without oophorectomy areat no risk from endometrial proliferation and can receive unopposed17β-oestradiol. However, for women with an intact uterus, 17β-oestradioltherapy may conveniently be combined with a progestogen to reduce therisk of endometrial carcinoma.

Progestogens which can be delivered vaginally, either alone or incombination with an oestrogen, using the device according to theinvention include any progestogens known to be suitable for use inhormonal replacement therapy and in contraception. Preferredprogestogens include progesterone, medroxyprogesterone, norethisterone,norethisterone acetate and trimegestone. Convenient amounts ofprogestogen present in the device are from 1 to 50% by weight,preferably up to 15% by weight, more preferably from 5 to 15% by weight.

Other actives which can be administered using the device in accordancewith the invention and their therapeutic use are listed by way ofexample only in the following table:

    ______________________________________                                        ACTIVE            CATEGORY                                                    ______________________________________                                        Fluphenazine      Antidepressants/Anxiolytics                                 Flupenthixol                                                                  Haloperidol                                                                   Buspirone         P.M.S. Anxiolytics                                          Alprazolam                                                                    Trifluoperzine                                                                Pyridoxine        P.M.S. Vitamin B6                                           Pridoxal                                                                      Pyridoxamine                                                                  Cholecalciferol   Vitamin D                                                   Dihydrotachysterol                                                            Ergocalciferol                                                                Alfacalcidol                                                                  d-Alpha Tocopherol                                                                              Vitamin E                                                   Clotrimazole      Antifungal                                                  Enconazole                                                                    Iltraconazole                                                                 Buprenorphine     Opioid Analgesics                                           Levorphanol                                                                   Phenoperidine                                                                 Fentanyl                                                                      Methadone                                                                     Mefanamic Acid    Non-Opioid Analgesics                                       Acyclovir         Antiviral                                                   Vidarabine                                                                    Arildone                                                                      Idoxuridine                                                                   Gestrinone        Endometriosis                                               Mifepristone                                                                  ______________________________________                                    

Intravaginal drug delivery devices in accordance with the invention canbe prepared by methods well known in the art, such as injection moldingtechniques or by melt extrusion of a polymer mixture. In this regard,the geometry of the device can be varied by the use of appropriatelysized moulds or appropriately sized extrusion dies.

The method used to surround the device with the polymer membrane willdepend on the geometry of the device. As mentioned previously, it ispreferred that the polymer membrane lies in close contact with thedevice. This may be achieved in a number of ways, for example usinginjection moulding or extrusion techniques. Other techniques which maybe used include coating of the device by a dipping process or winding anelongate strip of the polymer in the manner of a bandage around thedevice. Alternatively, a sheet of the polymer material may be wrappedaround the device and secured in position e.g. using adhesive, weldingor mechanical means such as stapling or stitching.

A preferred technique for wrapping the device comprises providing thedevice with a loose polymer sleeve and then removing the air using knownvacuum sealing techniques such that the sleeve forms a tight seal aroundthe device.

Viewed from a further aspect, the invention provides a method for themanufacture of an intravaginal drug delivery system in accordance withthe invention, said method comprising the step of providing, preferablysubstantially surrounding, a polymer matrix containing at least oneactive agent with a removable polymer membrane arranged to absorb excessactive agent.

Viewed from a yet further aspect, the invention provides a method forthe manufacture of an intravaginal drug delivery system in accordancewith the invention, said method comprising the following steps:

(a) dispersing at least one active agent, e.g. an oestrogen and/or aprogestogen, in a polymer matrix whereby to form a core;

(b) optionally surrounding said core with a rate-controlling sheath; and

(c) providing the resulting device with a removable polymer membranecapable of absorbing excess active agent.

Viewed from another aspect, the invention provides a process forpreparing a ready-to-use intravaginal drug delivery device, said processcomprising removal of a polymer wrapping from an intravaginal device orpart as herein described.

The present invention will now be further described by way of thefollowing non-limiting examples and with reference to the accompanyingfigures in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 illustrate the release of ethinyl estradiol (EE) andnorethindrone acetate (NA) from rings in accordance with the inventionhaving a core diameter of 2 mm, a sheath diameter of 7.6 mm and a sheaththickness of 2.8 mm.

FIGS. 3 and 4 illustrate the release of 17β-estradiol (E₂) from rings inaccordance with the invention having a core diameter of 4.5 mm, a sheathdiameter of 7.6 mm and a sheath thickness of 1.55 mm.

FIGS. 5 and 6 illustrate the release of ethinyl estradiol (EE) fromrings in accordance with the invention having a core diameter of 3 mm, asheath diameter of 7.6 mm and a sheath thickness of 2.3 mm.

EXAMPLE 1

A silicone mix was prepared by mixing 97% by weight ofpolydimethylsiloxane (Silastic 3099® available from Dow Corning) with2.5% by weight of the cross-linking agent n-propylorthosilicate (mix 1).10% by weight of ethinyl estradiol (EE) was then added to a firstportion of mix 1 and mixed thoroughly.

Appropriate quantities of the resulting mixture were then weighed and0.5% by weight of the catalyst stannous octoate was added and mixed forone minute. The final mix was then injected into 2 mm core moulds andsubsequently cured at 80° C. for two minutes. Ethinyl estradiol (EE)cores were then cut to length according to the dose required.

50% by weight of norethindrone acetate (NA) was added to a secondportion of mix 1 and mixed thoroughly. Appropriate quantities of theresulting mixture were then weighed and 0.33% by weight of the catalyststannous octoate was added and mixed for six minutes.

The final mix was then extruded using a 2 mm die and subsequently curedat 90° C. for one minute. Norethindrone acetate (NA) cores were then cutto length according to the dose required.

One NA and one EE core were then placed in a second mould. A sheath wasformed around the cores by two-stage injection moulding of mix 1together with 0.5% by weight of catalyst.

A number of the resulting rings were then smeared with a thin layer ofsilicone oil, wrapped in different polymers and left at ambienttemperature for three weeks. After this time the polymer wrappings wereremoved, the rings washed and release tested by suspension in 200 ml of0.133% benzalkonium chloride (BKC) solution. Release of NA and EE fromthese rings was compared with that from rings which had not been wrappedin any polymer material and which had been stored under similarconditions for a period of three weeks (control).

Tables 1 and 2 below and attached FIGS. 1 and 2 illustrate the rate ofrelease of ethinyl estradiol (EE) and norethindrone acetate (NA) fromthese rings.

                  TABLE 1                                                         ______________________________________                                        first day release of EE from a ring designed to                               deliver 25 μg of EE before and after wrapping with                         polyurethane or polyvinyl chloride.                                                   EE release (μg)                                                                            Polyvinyl                                             Time (hours)                                                                            Polyurethane  chloride Control                                      ______________________________________                                        0.25      0.0           13.2     20.8                                         0.5       0.0           19.3     29.6                                         1.0       0.0           27.5     41.6                                         2.0       0.0           39.9     59.9                                         4.0       0.0           55.1     81.0                                         6.0       0.0           68.1     96.5                                         24.0      38.2          132.1    171.8                                        ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        first day release of NA from a ring designed to                               deliver 1000 μg of NA before and after wrapping with                       polyurethane or polyvinyl chloride.                                                   NA release (μg)                                                                            Polyvinyl                                             Time (hours)                                                                            Polyurethane  chloride Control                                      ______________________________________                                        0.25      45.0          91.0     104.0                                        0.5       80.0          159.0    190.0                                        1.0       131.0         263.0    320.0                                        2.0       216.0         425.0    525.0                                        4.0       329.0         654.0    765.0                                        6.0       432.0         839.0    948.0                                        24.0      1031.0        1609.0   1669.0                                       ______________________________________                                    

EXAMPLE 2

A silicone mix was prepared by mixing 97% by weight ofpolydimethylsiloxane (Silastic 3099® available from Dow Corning) with2.5% by weight of the cross-linking agent n-propylorthosilicate. Theresulting mix was then blended in a ratio of 89% by weight with 11% byweight of isopropyl myristate (mix 1). 5% by weight of 17β-estradiol(E₂) was then added and mixed thoroughly.

Appropriate quantities of the above mix were then weighed and 0.5% byweight of the catalyst stannous octoate was added and mixed for oneminute. The final mix was then injected into 4.5 mm core moulds andsubsequently cured at 80° C. for two minutes.

The active cores were then removed from the moulds and placed in asecond mould. A sheath was then formed around the core by two-stageinjection moulding of mix 1 together with 0.5% by weight of catalyst.

A number of the resulting rings were then smeared with a thin layer ofsilicone oil, wrapped in different polymers and left at ambienttemperature for three weeks. After this time the polymer wrappings wereremoved, the rings washed and subjected to in vitro release testing inone liter of water at 37° C. Release of E₂ from these rings was comparedwith that from rings which had not been wrapped in any polymer materialand which had been stored under similar conditions for a period of threeweeks (control).

Table 3 below and attached FIGS. 3 and 4 illustrate the rate of releaseof E₂ from these rings.

                  TABLE 3                                                         ______________________________________                                        first day release of E.sub.2 from a ring designed to                          deliver 200 μg of E.sub.2 before and after wrapping with various           polymer materials.                                                            E.sub.2 release (μg)                                                       Time  Control Silicone PVC   PE/PP  PE/PA  PMP                                ______________________________________                                        0.5   55.3    31.8     31.2  33.6   32.2   30.2                               1.0   85.3    47.2     47.8  49.6   48.6   44.4                               2.0   114.7   69.6     68.5  74.8   75.2   67.9                               3.0   154.9   106.9    88.9  94.8   97.3   89.9                               4.0   178.2   110.3    109.7 131.6  115.9  106.2                              6.0   209.1   136.2    136.5 150.4  148.4  149.6                              24.0  408.0   314.0    322.3 339.4  326.4  306.9                              ______________________________________                                         PVC = polyvinyl chloride                                                      PE = polyethylene                                                             PP = polypropylene                                                            PA = polyamide                                                                PMP = polymethylpentene                                                  

EXAMPLE 3

Intravaginal rings were prepared in accordance with Example 1 using 3 mmcores. A number of the resulting rings were then vacuum wrapped inpolyurethane and left at ambient temperature.

After periods of 1 week, 2 weeks and 3 weeks of wrapping, thepolyurethane wrapping was removed and the rings were release tested inaccordance with the procedure given in Example 1. Release of ethinylestradiol (EE) from these rings was compared with that from rings whichhad not been wrapped in any polymer material and which had been storedunder similar conditions (control).

Attached FIGS. 5 and 6 illustrate the rate of release of EE from theserings. These clearly show that the first 10 days of release of EE isimproved by the wrapping process.

What is claimed is:
 1. An intravaginal drug delivery device comprisingat least one active agent dispersed in a polymer matrix, wherein theconcentration of active agent at the outer surface of the device at thetime of use is not substantially higher than the concentration of theactive agent in the remainder of the device.
 2. A device as claimed inclaim 1 wherein the concentration of active agent at the outer surfaceof the device is substantially lower than the concentration of theactive agent in the remainder of the device.
 3. A device as claimed inclaim 1 wherein said active agent comprises an oestrogen and/or aprogestogen.
 4. A method of contraception of the human or non-humanfemale body, said method comprising intravaginally administering to saidbody a device as claimed in claim
 3. 5. A method of treatment of thehuman or non-human female body to combat conditions resulting fromoestrogen deficiency, said method comprising intravaginallyadministering to said body a device as claimed in claim
 3. 6. A processfor preparing a ready-to-use intravaginal drug delivery device, saidprocess comprising removal of a polymer wrapping from an intravaginalpart, said intravaginal part comprising at least one active agent in apolymer matrix.
 7. A process for preparing a ready-to-use intravaginaldrug delivery device, said process comprising removal of a polymerwrapping from an intravaginal device, said intravaginal devicecomprising at least one active agent dispersed in a polymer matrix,wherein the concentration of active agent at the outer surface of thedevice at the time of use is not substantially higher than theconcentration of the active agent in the remainder of the device.